Intravitreal 5-Fluorouracil and Heparin to Prevent Proliferative Vitreoretinopathy: Results from a Randomized Clinical Trial.

PURPOSE: Proliferative vitreoretinopathy (PVR) is the major cause for surgical failure after primary rhegmatogenous retinal detachment (RRD). So far, no therapy has been proven to prevent PVR. Promising results for 5-fluorouracil (5-FU) and low-molecular weight heparin (LMWH) in high-risk eyes have been reported previously. The objective of this trial was to examine the effect of adjuvant intravitreal therapy with 5-FU and LMWH compared with placebo on incidence of PVR in high-risk patients with primary RRD. DESIGN: Randomized, double-blind, controlled, multicenter, interventional trial with 1 interim analysis. PARTICIPANTS: Patients with RRD who were considered to be at high risk for PVR were included. Risk of PVR was assessed by noninvasive aqueous flare measurement using laser flare photometry. METHODS: Patients were randomized 1:1 to verum (200 mg/ml 5-FU and 5 IU/ml dalteparin) and placebo (balanced salt solution) intravitreally applied during routine pars plana vitrectomy. MAIN OUTCOME MEASURES: Primary end point was the development of PVR grade CP (full-thickness retinal folds or subretinal strands in clock hours located posterior to equator) 1 or higher within 12 weeks after surgery. For grading, an end point committee assessed fundus photographs. Secondary end points included best-corrected visual acuity and redetachment rate. A group sequential design with 1 interim analysis was applied using the O'Brien and Fleming boundaries. Proliferative vitreoretinopathy grade CP incidence was compared using a Mantel-Haenszel test stratified by surgeon. RESULTS: A total of 325 patients in 13 German trial sites had been randomized (verum, n = 163; placebo, n = 162). In study eyes, mean laser flare was 31 ± 26 pc/ms. No significant difference was found in PVR rate. Primary analysis in the modified intention-to-treat population results were: verum 28% vs. placebo 23% (including not assessable cases as failures); odds ratio [OR], 1.25; 95% confidence interval [CI], 0.76-2.08; P = 0.77. Those in the per-protocol population were: 12% vs. 12%; OR, 1.05; 95% CI, 0.47-2.34; P = 0.47. None of the secondary end points showed any significant difference between treatment groups. During the study period, no relevant safety risks were identified. CONCLUSIONS: Rate of PVR did not differ between adjuvant therapy with 5-FU and LMWH and placebo treatment in eyes with RRD.

Ocular and Systemic Complement Activation during Anti-Vascular Endothelial Growth Factor Treatment and Age-Related Eye Disease Study 2 Dietary Supplementation in Neovascular Age-Related Macular Degeneration.

PURPOSE: The aim of this study was to investigate the influence of dietary supplementation using Age-Related Eye Disease Study 2 (AREDS2) on complement activation in patients with neovascular age-related macular degeneration (nAMD) under ongoing treatment. METHODS: In this prospective, single-center, controlled, open-label investigator-initiated trial, eligible nAMD patients were randomized at a ratio of 1:1 in 2 groups: those with and without dietary AREDS2 supplementation for 4 weeks. Zinc, plasma, and aqueous humor (AH) complement levels were quantified via enzyme-linked immunosorbent assays. RESULTS: Fifty of 62 enrolled patients completed the trial (AREDS2 n = 27, controls n = 23). Systemic zinc and complement levels were not different at baseline between the 2 groups (p > 0.1). At the final visit, systemic zinc levels were significantly higher in the AREDS2 group (10.16 ± 2.08 µmol/L; 8.66 ± 1.17 µmol/L; p = 0.007), whereas systemic and AH complement levels were not different (p > 0.1). In both groups, no significant change was observed in systemic levels of C3, C3a, FH, FI, and sC5b-9 (p > 0.1). Only systemic complement component Ba showed an increase from baseline to the end visit (p = 0.01). This increase was higher in the control group (p = 0.02) than in the AREDS2 group (p = 0.23). CONCLUSIONS: Short-term dietary AREDS2 supplementation leads to a significant increase in systemic zinc levels without any influence on complement activation levels.

Dynamics of structural reversal in Bruch's membrane opening-based morphometrics after glaucoma drainage device surgery.

PURPOSE: Structural reversal of disc cupping is a known phenomenon after trabeculectomy. The aim of this retrospective, longitudinal, cross-sectional analysis was to evaluate the postoperative dynamics of Bruch's membrane opening-based morphometrics of the optic nerve head following glaucoma drainage device surgery. METHODS: Forty-three eyes, treated by glaucoma drainage device surgery, were included in the study. Individual changes in the spectral domain optic coherence tomography (SD-OCT) parameters Bruch's membrane opening minimum rim width (BMO-MRW), Bruch's membrane opening minimum rim area (BMO-MRA) and peripapillary retinal nerve fiber layer (RNFL) thickness as well as mean defect in 30-2 perimetry were analyzed. Changes were correlated to postoperative intraocular pressure levels over time. Available follow-up visits were aggregated and grouped into a short-term follow-up (20 to 180 days after surgery), a midterm follow-up (181 to 360 days after surgery) and a long-term follow-up (more than 360 days after surgery). RESULTS: In short-term follow-up, BMO-MRW and BMO-MRA increased significantly (p <= 0.034). This increase correlated negatively with the intraocular pressure at the time of the follow-up (Pearson's rho = - 0.49; p = 0.039). From 6 months after surgery on, there was no statistically significant change in BMO-MRW and BMO-MRA (p >= 0.207). RNFL thickness and mean defect of 30-2 perimetry showed no significant changes after GDD implantation (p >= 0.189). CONCLUSIONS: Lowering of intraocular pressure by glaucoma drainage device surgery leads to an increase of Bruch's membrane opening based parameters in the first 6 months after surgery. These changes have to be taken into account when evaluating patients' longitudinal follow-up after glaucoma drainage device implantation.

Impact of ab-interno trabeculectomy on Bruch's membrane opening-based morphometry of the optic nerve head for glaucoma progression analysis.

PURPOSE: To analyze the longitudinal change in Bruch's membrane opening minimal rim width (BMO-MRW) and circumpapillary retinal nerve fiber layer (RNFL) thickness using spectral domain optical coherence tomography (SD-OCT) after glaucoma surgery via ab-interno trabeculectomy in adult glaucoma patients. METHODS: Retrospective audit of 65 eyes of 65 participants undergoing ab-interno trabeculectomy using electroablation of the trabecular meshwork. In 53 eyes, surgery was combined with phacoemulsification and posterior chamber lens implantation. Pre- and postoperative SD-OCT examinations of the optic nerve head (ONH), intraocular pressure (IOP), and visual field data were analyzed. Longitudinal change in morphometric SD-OCT parameters of the ONH was compared and correlated to change in IOP and visual field function. RESULTS: BMO-MRW increased significantly between baseline (BL) and follow-up (FU) within the first 6 months after surgery (BL = 167.85 ± 90 µm; FU = 175.59 ± 89 µm; p = 0.034). This increase correlated with postoperative lowering of IOP (rho = - 0.41; p = 0.016). Nine months after surgery (range, 7-12 months), there was no significant change in BMO-MRW (BL = 196.79 ± 79; FU = 196.47 ± 85 µm; p = 0.95), while in later follow-up, a decrease of BMO-MRW was found (BL = 175.18 ± 78; FU = 168.65 ± 72; p = 0.05). RNFL thickness was unchanged in early (p > 0.16) and significantly decreased in later follow-up (p = 0.009). Mean deviation (MD) of visual field function did not show a significant change before and after surgery. CONCLUSION: Electroablative ab-interno trabeculectomy leads to a significant transient mild increase in BMO-MRW. This increase was shown to correlate with IOP lowering. Significant loss of BMO-MRW in later follow-up may reflect insufficient IOP reduction by surgery. The parameters RNFL thickness and MD seem less impacted directly by surgery.

Prophylactic intravitreal 5-fluorouracil and heparin to prevent proliferative vitreoretinopathy in high-risk patients with retinal detachment: study protocol for a randomized controlled trial.

BACKGROUND: Proliferative vitreoretinopathy (PVR) is the major cause for postoperative failure after vitreo-retinal surgery for primary rhegmatogenous retinal detachment (RRD). Adjunct pharmaceutical therapy was found to be ineffective once PVR is established. Preliminary data suggest that prevention of PVR yields better functional outcome. So far, there is no standard therapy to prevent PVR. METHODS/DESIGN: This is a randomized, double-blind, controlled, multicenter, interventional trial with one interim analysis. High-risk patients for PVR with primary RRD will be allocated equally to the following treatment arms: (a) verum: intraoperative adjuvant application of 5-fluorouracil (5-FU) and low-molecular-weight heparin (LMWH) via intraocular infusion during routine pars plana vitrectomy (PPV) and (b) placebo: routinely used intraocular infusion with balanced salt solution during routine PPV. PVR risk is assessed by non-invasive aqueous flare measurement by using laser flare photometry. The primary endpoint of the trial is the occurrence of PVR grade CP (C: full-thickness retinal folds or subretinal strands in clock hours; P: located posterior to equator) 1 or higher within 12 weeks after treatment. Secondary endpoints include PVR grade CA (A: located anterior to equator), best corrected visual acuity, number and extent of surgical procedures to achieve retinal re-attachment, and occurrence of drug-related adverse events within 12 weeks. It is assumed, on the basis of previously published results, that the incidence of PVR grade CP 1 is 35% in the control group and that a reduction by one third would be clinically relevant. Given the sequential design and adjustment for a dropout rate of 5%, a total sample size of 560 patients (280 per group) was calculated to ensure a power of 80% for the confirmatory analysis. DISCUSSION: The present trial uses intraoperative intravitreal 5-FU and LMWH as a prophylactic therapy in high-risk patients with primary RRD, aiming to reduce the incidence of PVR in the group that receives the trial drug. Using laser flare photometry to identify high-risk patients for PVR, this trial will test the effectiveness of a simple treatment to prevent PVR. TRIAL REGISTRATION: EudraCT no.: 2015-004731-12, registered October 21, 2015; ClinicalTrials.gov Identifier: NCT02834559 , registered July 12, 2016. Protocol version: Version 02. Date: September 18, 2016.

Structural Reversal of Disc Cupping After Trabeculectomy Alters Bruch Membrane Opening-Based Parameters to Assess Neuroretinal Rim.

OBJECTIVE: To assess the impact of trabeculectomy for glaucoma on morphometric neuroretinal parameters of the optic nerve head (ONH) using spectral-domain optical coherence tomography (SD-OCT). DESIGN: Retrospective, interventional case series. METHODS: Participants: Eighty-eight eyes of 88 patients who underwent trabeculectomy with mitomycin C in 2016. INTERVENTION: All patients underwent trabeculectomy in 1 eye (study eye) and had evaluable SD-OCT examinations of the ONH to measure neuroretinal tissue before and at least at 1 of the 3-, 6-, and 12-month follow-up time points after surgery. MAIN OUTCOME MEASURES: Longitudinal change in Bruch membrane opening minimum rim width (BMO-MRW), Bruch membrane opening minimum rim area (BMO-MRA), peripapillary retinal nerve fiber layer (RNFL) thickness, intraocular pressure (IOP), and mean deviation in perimetry. RESULTS: In study eyes, BMO-MRW significantly increased postsurgically comparing baseline and follow-up examinations at 3 months (P = .012), at 6 months (P = .007), and at 1 year (P = .010) after trabeculectomy. The increase in BMO-MRW 6 months after surgery correlated with IOP reduction (r = 0.48; P = .001). BMO-MRA showed an equal increase (P ≤ .034). RNFL thickness remained stable between baseline and follow-up at 3, 6, and 12 months and showed a moderate loss after 18 months (P = .021) of follow-up. CONCLUSIONS: Structural reversal of disc cupping after trabeculectomy markedly influences Bruch membrane opening-based parameters for up to more than 1 year. Improvement in morphometry seems to correlate with the reduction of IOP while visual field function appears not to be influenced. In longitudinal follow-up of glaucoma patients by SD-OCT, evaluation of BMO-based parameters necessitates to reflect bias caused by surgery.